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NNNHNCH3NHNONCH3Imatinib (STI571)
Dasatinib (BMS-354825)300x1xBinds active conformationBinds
inactive conformation Dasatinib is a SRC/ABL inhibitor that is much
more potent than imatinib in vitro1Differential binding of
dasatinib (BMS-354825) and imatinib to ABL kinase
2BCR-ABL kinase domain point mutationBCR-ABL
overexpressionBCR-ABL-independent resistanceaa(exception:
T315I)r(exception: SRC-driven cases)Dasatinib: predicted effects
against mechanisms of clinical resistance to imatinib3Dasatinib 70
mg BID in CP-CML: 24 Month ResultsCCyR Achieved for the First Time
in Many Patients0255075100% patients achieving CCyR19TotalStone R
et al. ASH meeting, 2007, abstract #734.53Prior CCyR on
imatinib(median duration tx > 3yrs)CCyR on dasatinib4Complete
CyRPartial CyRComplete HRNo responseResponse by individual baseline
BCR-ABL mutationDasatinib 70 mg BID in chronic phase CML Cellular
IC50 (nM)DasatinibImatinib nM244V1.32000 17L248V1500
9G250E/V1.813503900 23Y253F/H/K1.310>10000
14E255K/V5.61344008400 10D276G1500 3T315I>1000>10000
3F317L7.41050 4M351T1.1930 15E355G400 6F359C/I/V2.21200
8L387M2.01000 2H396P/R0.61.138504200 17Other 30Stone R et al. ASH
meeting, 2007, abstract #734.ASH 2007BMS Confidential - Not for
Further Copying or Distribution5Complete CyRPartial CyRComplete
HRNo responseResponse by individual baseline BCR-ABL
mutationDasatinib 70 mg BID in chronic phase CML Cellular IC50
(nM)DasatinibImatinib nM244V1.32000 17L248V1500 9G250E/V1.813503900
23Y253F/H/K1.310>10000 14E255K/V5.61344008400 10D276G1500
3T315I>1000>10000 3F317L7.41050 4M351T1.1930 15E355G400
6F359C/I/V2.21200 8L387M2.01000 2H396P/R0.61.138504200 17Other
30Stone R et al. ASH meeting, 2007, abstract #734.ASH 2007BMS
Confidential - Not for Further Copying or Distribution6Dasatinib
Inhibits Growth of 14/15 Imatinib-Resistant BCR-ABLExpressing Ba/F3
Cell Lines in
VitroQ252HBa/F3Bcr-AblE255KM351TM244VG250EQ252RY253FY253HE255VF317LE355GF359VH396RF486ST315IShah
et al. Science. 2004;305(5682):399-401.Normalized cell number after
48 hours of drug exposureConcentration of dasatinib
(nM)00.20.40.60.811.200.52.552550T315IParental Ba/F3
cellsF317L#77AP-CML
CML-MB
CML-LBMonthsProportion progression-free
Dasatinib in advanced CML and Ph+ ALL Progression-free
survival1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21N=46Median PFS = 3.7 moNo. progressed =
35
Ph+ ALLAP-CMLDombret et al, ASH 2006 (abstract #286)Cortes et
al, ASH 2006 (abstract #2160); Martinelli et al, ASH 2006 (abstract
#745)8Chronic Phase CML Treatment Landscape
EvolutionImatinibapproved by FDADasatinib approved for resistant or
intolerant CML 2000201020122008200620042002#You may not show or
distribute this item outside BMS.You may NOT discuss the
information in this item with customers.Speaker NotesSince initial
discovery of the Philadelphia chromosome in 19601 and FDA approval
of GLEEVEC (imatinib) in 2001,2 the treatment landscape of CML
continues to evolveRead as stated
References1. Wong S, Witte O. Annu Rev Immunol.
2004;22:247306.2. GLEEVEC (imatinib) Full Prescribing Information.
Novartis.
9Nilotinib has a better fit to the binding pocket
Rationally designed highly specific inhibitor of BCR-ABL 30X
more potent than imatinib; maintains target specificity No
significant effect on other kinases (Src, FLT3, VEGFR, EGFR, InsR,
RET, MET, IGFR, etc)Imatinib IC50 669 nM Nilotinib IC50 25nMASH
2007BMS Confidential - Not for Further Copying or
Distribution10Nilotinib ABL > PDGFR > KIT(Cell prolif. IC50)
(24 nM) (53 nM) (158 nM)
Imatinib PDGFR > KIT > ABL(Cell prolif. IC50) (39 nM) (120
nM) (649 nM)Nilotinib has no significant effect on other kinases
evaluated(including SRC, FLT3, VEGFR, EGFR, InsR, RET, MET, IGFR,
etc) at concentrations 1- 10% 1%Nilotinib 300 mg BID
(n=258)Imatinib (n=264)Reasons for unevaluable samples included:
Atypical transcripts: 5 patients on nilotinib, 2 patients on
imatinibMissing samples: 4 patients on nilotinib, 5 patients on
imatinibDiscontinuation: 15 patients (including 1 progression) on
nilotinib, 12 patients (including 1 progression) on
imatinib*Calculated from total number of evaluable patients with
PCR assessments at 3 months.BCR-ABL 10% >1- 10%
1%30ENESTnd 5-Year UpdateData cutoff: May 22, 201330OS by
BCR-ABL Levels at 3 MonthsNilotinib 300 mg BIDImatinib 400 mg QDP =
.4871P = .0007OS by 5 YearsaBCR-ABL Level 1%> 1% to 10%>
10%Censored Observations Pts Evt Cen145 6 1398928724519
10090807060504030201000123456 Patients Alive, %Time Since
Randomization, Calendar Years10090807060504030201000123456Time
Since Randomization, Calendar YearsOS by 5 YearsaP < .0001P =
.087399.2%95.3%BCR-ABL Level 1%> 1% to 10%> 10%Censored
Observations
Pts Evt Cen432 41133 113288 1672
Cen, censored; EMR, early molecular response; Evt, events; Pts,
patients.a OS rates reported consider each year to consist of
twelve 28-day cycles.Patients with EMR failure (BCR-ABL > 10% at
3 months) have significantly worse 5-year OSRates of EMR failure
are lower on nilotinib 300 mg BID vs imatinib79.5%95.7%97.6%81.9%
Patients Alive, %EMR Failure: 9% of ptsEMR Failure: 33% of
pts31ENESTnd 5-Year UpdateData cutoff: May 22, 201331Proportion of
Patients With MR4.5 by BCR-ABL Levels at 3 Months58%28%4%P = .0001P
= .013570%52%8%P = .0046P = .0001MR4.5 by 4 YearsaMR4.5 by 5
YearsaBCR-ABL Level 1%> 1% to 10%> 10%Pts1448924
10090807060504030201000123456 Patients With MR4.5, %Time Since
Randomization, Calendar YearsMR4.5 by 4 YearsaMR4.5 by 5
Yearsa65%24%5%P < .0001P = .000167%34%15%P = .0001P =
.0016BCR-ABL Level 1%> 1% to 10%> 10%Pts 4313388
10090807060504030201000123456 Patients With MR4.5, %Time Since
Randomization, Calendar Yearsa Cumulative response rates reported
consider each year to consist of twelve 28-day cycles.BCR-ABLIS 1%:
16% of ptsBCR-ABLIS 1%: 56% of ptsNilotinib 300 mg BIDImatinib 400
mg QDPatients with BCR-ABL 1% at 3 months have significantly higher
rates of MR4.5 by 5 yearsMore patients achieve BCR-ABL 1% at 3
months on nilotinib 300 mg BID vs imatinib32ENESTnd 5-Year
UpdateData cutoff: May 22, 201332ConclusionsAt 5 years of
follow-up, rates of event-free survival, progression-free survival,
and overall survival were higher in patients treated with nilotinib
than imatinibNilotinib demonstrated higher rates of early and
deeper molecular response, including MR4.5, and a reduced risk of
progressionBy 5 years, more than half of nilotinib-treated patients
had achieved MR4.5, a key eligibility criterion for many
treatment-free remission studiesSide effects that appear unique to
nilotinib include pancreatitis, hyperglycemia, EKG changes and
peripheral arterial occlusive events. 33ENESTnd 5-Year UpdateData
cutoff: May 22, 201333Evolving CML Treatment LandscapeGLEEVEC
(imatinib)approved by FDA1TASIGNA (nilotinib) for resistant or
intolerant CP Ph+ CML approved by FDA31st-Line CP Ph+ CML approval
of TASIGNA3SPRYCEL (dasatinib) for resistant or intolerant CP Ph+
CML approved by FDA22000201020122008200620042002Ponatinib approved
for resistant or intolerant CML Bosutinib approved for resistant or
intolerant CML #You may not show or distribute this item outside
BMS.You may NOT discuss the information in this item with
customers.Speaker NotesSince initial discovery of the Philadelphia
chromosome in 19601 and FDA approval of GLEEVEC (imatinib) in
2001,2 the treatment landscape of CML continues to evolveRead as
stated
References1. Wong S, Witte O. Annu Rev Immunol.
2004;22:247306.2. GLEEVEC (imatinib) Full Prescribing Information.
Novartis.
34Database lock of 24-Mar-2014Primary end point: confirmed CCyR
by 12 months77% dasatinib vs. 66% imatinib (P=0.007)1DASISION
(CA180-056) Study Design5-yearfinal resultsRandomized aImatinib 400
mg QD (n=260)Dasatinib 100 mg QD (n=259)Treatment-nave CML-CP
patients (N=519)108 centers26 countriesEnrollment: September
2007December 2008a Stratified by EURO (Hasford) risk score.1.
Kantarjian H et al. N Engl J Med 2010;362:226070.#DASISION 5-Year
Final Study Results35Cumulative MMR Rates Over TimeMonths Since
Randomization% With MMRDasatinib 100 mg QDNImatinib 400 mg
QD260259By 1 yearBy 2 yearsBy 3 yearsBy 4 yearsBy 5
years28%46%55%60%64% 46% 64% 67% 73%
76%061218243036424854601009080706050403020100p=0.0022#DASISION
5-Year Final Study
Results36061218243036424854601009080706050403020100Cumulative MR4.5
Rates Over TimeBy 1 yearBy 2 yearsBy 3 yearsBy 4 yearsBy 5
years3%8%13%23%33% 5%19%24%34%42%p=0.0251MR4.5, BCR-ABL (IS)
0.0032% (for subjects with B2a2 and B3A2 transcripts). Months Since
Randomization% With MR4.5Dasatinib 100 mg QDNImatinib 400 mg
QD260259#DASISION 5-Year Final Study Results37Dasatinib 100 mg QD
(n=259)Imatinib 400 mg QD (n=260)BCR-ABL at 3
Months10%(84%)>10%(16%)10% (64%)>10% (36%)CCyR, %94419259MMR,
%87388141MR4.5, %5454812Best 5-Year Responses by Molecular
Responseat 3 Months#DASISION 5-Year Final Study Results38Dasatinib
100 mg QD(n=259)Imatinib 400 mg QD(n=260)BCR-ABL at 3 Months10%
(84%)>10%(16%)P value10%(64%)>10%(36%)P valueEstimated 5-year
OS, %94810.002895810.0003Estimated 5-year PFS,
%89720.0014937210%n=85Transformation to AP/BP b, n (%)6 (3)5 (14)5
(3)13 (15)Patients, nOverall transformations to
AP/BP4.6%7.3%Dasatinib n=259Imatinib n=260On studyDuring follow-up
beyond discontinuationTransformation to AP/BP CML by 5 Yearsa One
dasatinib and one imatinib patient transformed but did not have
3-month molecular assessments.b Including follow-up beyond
discontinuation (intent to treat).#DASISION 5-Year Final Study
Results40Conclusions5-Year follow-up demonstrates:Deeper molecular
responses with dasatinib versus imatinibMore optimal molecular
responses with dasatinib versus imatinibFewer transformations to
AP/BPAchievement of BCR-ABL 10% at 3 months is associated with
significantly higher PFS and OS by 5 years- BCR-ABL 10% at 3
months: dasatinib 84% versus imatinib 64%By 5 years, 42% of
dasatinib-treated patients had achieved MR4.5, a key eligibility
criterion for many treatment-free remission studiesSide effects
that appear unique to dasatinib include pleural effusion and
pulmonary arterial hypertension.
#DASISION 4-Year Follow-up41
Chart116505634339
NilotinibImatinib
Sheet1Nilotinib165633Imatinib50349
